NAD-dependent isocitrate dehydrogenase as a novel target of tributyltin in human embryonic carcinoma cells.
NAD-dependent isocitrate dehydrogenase as a novel target of tributyltin in human embryonic carcinoma cells.
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DOI：
10.1038/srep05952
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发表时间：
2014-08-05
影响因子：
4.6
通讯作者：
Kanda Y
中科院分区：
文献类型：
--
作者：
Yamada S;Kotake Y;Demizu Y;Kurihara M;Sekino Y;Kanda Y
Tributyltin (TBT) is known to cause developmental defects as endocrine disruptive chemicals (EDCs). At nanomoler concentrations, TBT actions were mediated by genomic pathways via PPAR/RXR. However, non-genomic target of TBT has not been elucidated. To investigate non-genomic TBT targets, we performed comprehensive metabolomic analyses using human embryonic carcinoma NT2/D1 cells. We found that 100 nM TBT reduced the amounts of α-ketoglutarate, succinate and malate. We further found that TBT decreased the activity of NAD-dependent isocitrate dehydrogenase (NAD-IDH), which catalyzes the conversion of isocitrate to α-ketoglutarate in the TCA cycle. In addition, TBT inhibited cell growth and enhanced neuronal differentiation through NAD-IDH inhibition. Furthermore, studies using bacterially expressed human NAD-IDH and in silico simulations suggest that TBT inhibits NAD-IDH due to a possible interaction. These results suggest that NAD-IDH is a novel non-genomic target of TBT at nanomolar levels. Thus, a metabolomic approach may provide new insights into the mechanism of EDC action.
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